Treatment landscape for metastatic breast cancer no longer in a ‘primitive place’
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Key takeaways:
- Researchers are examining the use of immunotherapy plus PARP inhibitors to treat triple-negative disease.
- Tools are needed for earlier diagnosis of all metastatic breast cancer types.
The treatment landscape for metastatic breast cancer has evolved tremendously within the past 2 decades.
Researchers now have a better understanding on what is driving individual malignancies and within the past 5 years have identified use for targeted therapies that are prolonging lives and are accompanied with fewer side effects.
“Ten to 20 years ago, the treatment landscape for metastatic breast cancer was in a much more primitive place,” Jane L. Meisel, MD, associate professor in the department of hematology and medical oncology at Winship Cancer Institute of Emory University, told Healio. “Chemotherapy was the main treatment choice, patients had shorter lifespans and there were many side effects from treatment. There is so much going on in this space.
“People are living longer and better lives, which is amazing, and because people are living longer, we are able to turn metastatic disease into almost more of a chronic disease for certain patients,” she continued. “We are paying more attention to side effects and quality of life, which wasn’t much of a priority before because people weren’t living as long. Ensuring that patients feel empowered to help make decisions in their treatment plan, their quality of life and side effects are being appropriately managed, are now key.”
Triple-negative disease
The KEYNOTE-355 trial showed statistically significant improvements in PFS and OS with the addition of pembrolizumab (Keytruda, Merck) to first-line chemotherapy among patients with PD-L1-positive metastatic triple-negative breast cancer.
As Healio previously reported, results of the trial served as the basis for FDA approval of the combination among those with metastatic triple-negative disease.
Among patients with a PD-L1 CPS of 10 or higher, researchers observed median OS of 23 months in the pembrolizumab group compared with 16.1 months in the placebo group (HR = 0.73; 95% CI, 0.55-0.95).
Moreover, those with a CPS of 10 or higher derived the greatest objective response rate benefit with pembrolizumab vs. chemotherapy (52.7% vs. 40.8%), followed by patients with a CPS of 1 or higher (44.9% vs. 38.9%) and the intention-to-treat population (40.8% vs. 37%).
Of note, patients in all three groups experienced longer duration of response with the pembrolizumab combination.
Researchers reported grade 3 or higher treatment-associated adverse events among 68.1% of patients in the pembrolizumab group and 66.9% of patients in the placebo group, including anemia, neutropenia and nausea. Two deaths occurred in the pembrolizumab group due to treatment-associated adverse events.
“Immunotherapy has made a big difference in the lives of so many patients with triple-negative disease,” Meisel said. “There is still more interest in figuring out how to make tumors more immunogenic for those who don’t respond to immunotherapy and we are looking at a lot of different combinations, including immunotherapy plus [poly(ADP)-ribose polymerase (PARP)] inhibitors or immunotherapy combined with antibody-drug conjugates, to try to help patients who have not responded to immunotherapy effectively become immunotherapy responders.”
HER2 disease
For patients with HER2 metastatic breast cancer, the groundbreaking phase 3 DESTINY-Breast04 trial showed fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo) significantly extended PFS and OS compared with standard of care treatment among a cohort of patients with HER2-low metastatic disease — regardless of hormone receptor status.
“In the HER2 space, there are many interesting antibody-drug conjugates under investigation, as well as other HER2-targeted therapies that are being looked at. And some existing therapies are being looked at in novel combinations with each other to try and understand how to best target this population of patients with metastatic disease,” Meisel said.
As Healio previously reported, fam-trastuzumab deruxtecan-nxki also exhibited a manageable safety profile.
Researchers compared the safety and efficacy of trastuzumab deruxtecan with treatment of physician’s choice among 557 patients with HER2-low metastatic breast cancer who previously received between one and two prior lines of chemotherapy for metastatic disease.
Results showed median PFS of 9.9 months (95% CI, 9-11.3) among patients assigned trastuzumab deruxtecan compared with 5.1 months (95% CI, 4.2-6.8) among those assigned physician’s treatment choice (HR = 0.5; 95% CI, 0.4-0.63).
Researchers also reported longer median OS with trastuzumab deruxtecan (23.4 months; 95% CI, 20-24.8) compared with physician’s choice (16.8 months; 95% CI, 14.5-20) for an HR of 0.64 (95% CI, 0.49-0.84).
“Overall, these results establish that HER2-low metastatic breast cancer is a targetable population of breast cancer with trastuzumab deruxtecan as a new standard of care in this setting,” according to Shanu Modi, MD, medical oncologist at Memorial Sloan Kettering Cancer Center.
Estrogen-positive disease
There are many different trials investigating novel compounds in the estrogen-positive space, according to Meisel.
“Estrogen receptor down regulators is one example, and there are many different combination therapy options with anti-estrogen pills,” she said. “The CAPItello-291 trial was really interesting and led to the availability of a new antiestrogen combination treatment.”
Results of the randomized phase 3 CAPItello-291 trial showed that the addition of capivasertib (Truqap, AstraZeneca) to fulvestrant led to significant improvement in PFS among patients with hormone receptor-positive breast cancer. Capivasertib — an investigational AKT inhibitor — also appeared safe and exhibited a manageable toxicity profile.
Researchers assigned patients 1:1 to fulvestrant plus capivasertib (n = 355) or placebo (n = 353) and found that those assigned capivasertib experienced longer median PFS vs. placebo (7.2 months vs. 3.6 months; HR = 0.6; 95% CI, 0.51-0.71). Results also showed a higher ORR in the capivasertib group (22.9% vs. 12.2%).
Of note, more patients in the capivasertib group discontinued treatment (13% vs. 2.3%). Common grade 3 or higher adverse events with capivasertib included rash (12.1%), diarrhea (9.3%) and hyperglycemia (2.3%).
“Capivasertib plus fulvestrant has the potential to be a future treatment option for patients with hormone receptor-positive advanced breast cancer who have progressed on an endocrine-based regimen,” according to Nicholas C. Turner, MD, PhD, professor in the department of molecular oncology at The Institute of Cancer Research in London and consultant medical oncologist at The Royal Marsden NHS Foundation Trust.
Research needs
Looking ahead, Meisel said she hopes to see tools that will allow for earlier diagnosis of metastatic disease.
“There is a lot of ongoing research in the circulating tumor DNA space, examining the potential of early detection of metastatic disease in high-risk patients — even before it becomes evident on the scanner and before patients become symptomatic,” she said.
Another hope for future treatments is the creation of more targeted combination therapies that lead to long-term remission, Meisel continued.
“A lot of us have those few outlier patients where we start them on a targeted therapy for estrogen-positive metastatic disease or HER2-positive metastatic disease, and they do well on that treatment. Their disease sort of ‘melts away’ for years and years,” she said. “We then wonder if we cured their metastatic disease. But that is only the minority of the patient population and something that we don’t expect for all patients but is something that we hope for. It would be wonderful to be able to better understand who those super responders are, why their disease biology (responded) that way and how we can create more of those. Those are current research needs in this population.”
References:
- Modi S, et al. Abstract LBA3. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
- Rugo H, et al. Abstract GS01-05. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2023; San Antonio.
- Turner N, et al. Abstract GS3-04. Presented at: San Antonio Breast Cancer Symposium; Dec. 6-10, 2022.
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